Many patients receiving chemotherapy and/or ionizing radiation (IR) develop acute and residual (or long- term) bone marrow (BM) injury that limits the success of cancer treatment and adversely affects their quality of life. Acute myelosuppression is the result of the induction of apoptosis in the rapidly proliferating hematopoietic progenitor cells (HPCs) and to a lesser degree in the relatively quiescent hematopoietic stem cells (HSCs). Its clinical manifestations have been successfully managed by the use of various hematopoietic growth factors. In contrast, residual BM injury has been largely attributed to the induction of HSC senescence. However, neither the molecular mechanisms by which chemotherapy and/or IR induce HSC senescence have been clearly defined, nor has an effective treatment been developed to ameliorate residual BM injury. Recent studies from our laboratory and others provide new insights into HSC damage. First, we have found that exposure of mice to a sublethal dose of total body irradiation (TBI) perturbs the balance of reduction/oxidation (redox) reactions ONLY in HSCs, leading to a persistent and prolonged increase in reactive oxygen species (ROS) production. Second, HSCs are more sensitive to ROS-induced oxidative damage than HPCs and other hematopoietic cells. Moreover, it appears that ROS injures HSCs not by a nonspecific cytotoxic effect as previously hypothesized. Instead, the damage is at least partially mediated by induction of cellular senescence through redox-dependent activation of the p38 mitogen-activated protein kinase (p38)-p16lnk4a (p16) pathway. Based on these novel findings, we hypothesize that chemotherapy and IR cause residual BM injury by SELECTIVELY inducing HSC senescence through ROS-mediated activation of the p38-p16 pathway. Thus, we predict that antioxidants can be used to effectively mitigate residual BM injury. Moreover, antioxidant therapy provides additional benefits to cancer patients by suppressing chemotherapy- and IR-induced genetic instability, a primary cause of secondary tumors and a contributing factor to the development of tumor resistance. Therefore, this strategy offers the promise of significantly improving the quality of life and increasing the efficacy of chemotherapy and radiotherapy for cancer patients.